An integrative mutational and network analysis of pancreatic cancer reveals key genes, and signalling pathways

Pancreatic cancer (PC) is one of the most lethal malignancies, with an approximately 5% 5-year survival rate. Understanding the intricate network of interactions among the proteins of key pathways is critical for assessing the PC prognosis. Herein, we have carried out a systematic approach by collecting mutational data of genes involved in 10 PC studies with 6,325 PC samples from cBioPortal. A total of 15,088 genes were obtained, to which a mutational frequency cut-off of > 10 was applied. The 1,617 genes acquired after this filtration. These genes were stratified into five PC tiers (PC-TierII to PC-TierV), with PC-TierI comprising six frequently mutated genes icluding KRAS (73.40%), TP53 (51.20%), SMAD4 (18.70%), TTN (14.20%), CDKN2A (12.40%), MUC16 (6.70%) and PC-TierII including ARID1A (5.60%), RNF43 (5.20%), FLG (5.00%). These genes were then used for pathway enrichment analysis using the EnrichR suite, followed by co-expression interaction analysis via GeneMANIA. ACVR1B, KRAS, RBBP8, SMAD4, STK11, and TP53 were predicted to be associated with the PC (OMIM ID: 260350). PC has lower KRAS mutation counts closely related to ovarian and uterus cancers and top KRAS mutations are KRAS^G12D, KRAS^G12V, KRAS^G12C, KRAS^G12R and KRAS^G12A. We highlighted the interaction between the PC genes identified in this study in various pathways associated with PC such as RTK-RAS, WNT/β-Catenin, NOTCH, Hedgehog, TGF-β, along with protein interactions encoded by PC-related genes. Additionally, cross-library EnrichR pathway overlap analysis revealed highly interconnected extracellular matrix/integrin and neuronal signaling modules driven by recurrent collagen, laminin, ion-channel, and axon-guidance genes across multiple PC pathways. This PC gene list was compared with four PC gene panels. Invitae and Fulgent offer the broadest gene coverage (20/21), with 16 genes universally covered by all four providers, while GeneD and Prevention Genetics lag at 17 genes each, with critical gaps in rare cancer predisposition genes like TSC1, TSC2, and NF1. Overall, these findings refine the molecular landscape of PC and highlight key genes and pathways with potential clinical relevance.